Vaccine Timeline

Before Jenner and After COVID-19

Smallpox raged through Boston in 1721, ending in 844 deaths. During this epidemic, physician Zabdiel Boylston, at Cotton Mather's urging, variolated 248 people, thereby introducing variolation to the Americas. Of those variolated, six died. The case fatality for variolation was about 3%, and the disease case fatality was 14%. About 900 people left town for fear of catching the disease.

At Harvard, the chambermaid of Cotton Mather’s son Samuel contracted smallpox. Samuel’s brother Increase encouraged his father to have Samuel variolated by Boylston, and Samuel survived the procedure.

Mather was widely criticized for his role in promoting variolation: a primitive grenade was thrown through a window of his house. The attached note threatened “COTTON MATHER, You Dog, Dam you. I’ll inoculate you with this, with a Pox to you.”

Reacting to the Boston outrage against inoculation, Mather wrote:

“I never saw the Devil so let loose upon any occasion. The people who made the loudest Cry…had a very Satanic Fury acting them…. Their common Way was to rail and rave, and wish Death or other Mischiefs, to them that practis’d, or favour’d this devilish Invention.”

— Cotton Mather, quoted in The Life and Death of Smallpox by Ian Glynn and Jenifer Glynn

George Washington, commander-in-chief of the Continental Army, based at his headquarters in Morristown, New Jersey, ordered mandatory inoculation for troops if they had not survived a smallpox infection earlier in life—possibly in reaction to the inability of Benedict Arnold’s troops to capture Quebec from Britain the year before, when more than half of the colonial troops had smallpox. Recruits passing through Virginia were inoculated at Alexandria.

Edward Jenner tested the hypothesis that infection with cowpox could protect a person from smallpox infection.

Cowpox is an uncommon illness in cattle, usually mild, that can be spread from a cow to humans via sores on the cow. During an infection, dairy workers may have pustules on their hands. Sufferers can spread the infection to other parts of the body.

We know now that the cowpox virus belongs to the Orthopox family of viruses. Orthopox viruses also include horsepox virus, monkeypox virus, and variola virus, which causes smallpox.

On May 14, 1796, Jenner inoculated eight-year-old James Phipps with matter from a cowpox sore on the hand of milkmaid Sarah Nelmes. Phipps suffered a local reaction and felt poorly for several days but made a full recovery. In July 1796, Jenner inoculated Phipps with matter taken from a fresh human smallpox sore, as if he were variolating the boy, in an attempt to challenge the protection from cowpox. Phipps remained healthy. Jenner next demonstrated that cowpox matter transferred in a human chain, from one person to the next, provided protection from smallpox.

Jenner was not precisely sure about the nature of the cowpox material he used. He suspected that cowpox actually came from horsepox; in other words, he speculated that cows became infected with the same agent that caused a similar disease in horses. Recent genetic analysis of old samples of smallpox vaccine have revealed that the samples were more closely related to horsepox virus than cowpox virus. 

King Charles IV of Spain commissioned royal physician Francisco Xavier de Balmis to bring smallpox vaccination to the Spanish colonies in the New World. De Balmis departed on a ship with 22 abandoned children and a host of assistants, planning to vaccinate the boys in sets of two throughout the trip so that fresh pustules would be available at any given time. He eventually reached Caracas. Despite only one of the children still having a visible cowpox pustule, De Balmis initiated South American vaccination. (All 22 children were eventually settled, educated, and adopted in Mexico, at the Spanish government’s expense.)

Pasteur successfully prevented rabies in nine-year-old Joseph Meister by post-exposure vaccination.

Meister’s mother brought the boy, severely bitten by a rabid dog, to Pasteur in hopes of preventing the disease. Several factors made Pasteur’s potential involvement in the boy’s care controversial.

1. Pasteur had never before successfully used the vaccine on a human. (Pasteur’s notebooks indicated that two previous attempts had been made. One involved a 60-year-old man who left the hospital after only one injection and did not return. The other was 10-year-old girl, treated with one injection, who died before the second could be given.)
2. The concept of attenuation of viruses and bacteria was in its infancy at this time. Injecting a human with a disease agent, even a weakened one, was a new and controversial action.
3. Pasteur was not a medical doctor and might have faced serious consequences had Meister not survived the injections.

Pasteur felt certain that the boy would die from rabies infection if he did nothing. So he began the course of 13 injections, one each day, of vaccine made from rabbit nervous system tissue. Each successive injection contained less-attenuated (stronger) virus.

Meister never developed rabies, and the incident was regarded as a success. Later in life, Meister worked as caretaker of Pasteur’s tomb at the Institut Pasteur in Paris.

Waldemar Haffkine arrived in India to conduct tests of his cholera vaccine.

In his trials, he employed control and experimental groups, a relatively new practice for the time, and vaccinated more than 40,000 people. Though he was not always able to maintain rigorous controls, his methods would become useful models for future vaccine trials. His vaccine showed efficacy in many of the trial subgroups.

By mid-1896, Haffkine had concluded that the use of an initial attenuated vaccine was unnecessary, and so, as his trials continued, he tested only the more potent vaccine.

Mulford Company of Philadelphia (later Merck Sharp & Dohme) began to produce and test diphtheria antitoxin in the United States.

The New York City Health Department began producing diphtheria antitoxin this year as well. Deaths from the disease began to drop as the treatment was increasingly used.

A first step in producing diphtheria antitoxin involved incubating the bacteria and then determining which samples were of adequate strength to produce antitoxin. Workers grew the bacteria in test tubes and then tested the strength of the bacteria on guinea pigs.

“In a little animal weighing three hundred grams (about half a pound) we would inject, perhaps, one one-hundredth of a cubic centimeter, or one-fifth of a drop; in another would be injected one-half, and in a third one-quarter of this quantity."

“By keeping these animals under observation for a few days, we are enabled to detect just how large a quantity of this bouillon containing the living bacilli from each of the cultures is needed to destroy the life of the animal. When this has been determined, we select four or five of the most virulent cultures to use for the production of the toxines.” –WH Park and HM Biggs, Diphtheria Antitoxin

Park and Biggs described the method for producing serum from horses for use in diphtheria treatment. The horses were injected over time with increasing amounts of diphtheria toxin, starting with about 0.5 cubic centimeters (about 10 drops).

"When we can introduce from two hundred to three hundred cubic centimeters of strong toxine into the horse without producing serious symptoms, we can feel pretty certain that the horse's blood contains anti-toxine in sufficient amount to be used for healing purposes."

The serum was then processed and used to treat those suffering from diphtheria.

The U.S. Congress passed "An act to regulate the sale of viruses, serums, toxins, and analogous products," later referred to as the Biologics Control Act (even though "biologics" appears nowhere in the law). This was the first modern federal legislation to control the quality of drugs. This act emerged in part as a response to the 1901 St. Louis and Camden contamination events.

The Act created the Hygienic Laboratory of the U.S. Public Health Service to oversee manufacture of biological drugs. The Hygienic Laboratory eventually became the National Institutes of Health.

An enormous fundraising effort began when entertainer Eddie Cantor suggested on the radio that people send dimes to President Roosevelt at the White House to help fight polio. Within a few weeks, people had mailed 2,680,000 dimes to the President.

Other celebrities and then grass-roots organizers joined in the campaign. Over the years, this “March of Dimes” raised tens of millions of dollars, much of which went to the effort to find a vaccine.

Diphtheria outbreaks accompanied war and disruption in Europe: in 1943, there were 1 million cases in Europe, with 50,000 deaths (not including the USSR).

Smallpox appeared for the final time in New York City.

Eugene Le Bar, a merchant traveling from Mexico City to Maine with his wife, arrived in the city by bus, bringing the disease with him. Feeling ill, Le Bar went to Bellevue Hospital. Three days later he was transferred to the city’s contagious disease hospital. He died two days later.

Le Bar’s death was not immediately attributed to smallpox, but when the disease appeared in two other patients who had been at the contagious disease facility at the same time, the hospital staff notified the health department. Eugene Le Bar’s case of smallpox launched a massive vaccination program in the city, as the health department attempted to trace his steps before arriving at Bellevue Hospital and vaccinate anyone whose path he may have crossed. Health commissioner Israel Weinstein personally visited New York City Mayor William O’Dwyer to request $500,000 for the purchase of additional vaccine and to hire additional staff. O’Dwyer held a press conference in which he asked all residents who had not been recently vaccinated to be vaccinated against the disease. In the next month, 80% of the city’s residents were vaccinated—some 6.35 million people. In the end, the effort was judged a success: the total number of smallpox cases reached only 12, and the final death count was limited to two.

The Vaccine Advisory Committee approved a field test of Salk’s polio vaccine. The trial began the next day, with the vaccination of thousands of schoolchildren.

In all, over 1.3 million children participated in the trial. The trial was a randomized, double-blinded test, meaning that children were randomly assigned to either the control group or the vaccine group. Neither the children (nor their parents) nor health officials knew which children had received the vaccine and which had received the injected placebo fluid. (A smaller control group received no injection. Rather, officials observed them throughout the trial period for signs of polio infection.)

It would take almost a year to analyze the results and determine whether the vaccine provided protection against polio.

Albert Sabin forged a bond with Soviet health officials, who were interested in a cheaper alternative to Salk’s vaccine. Sabin had spent years studying and attenuating the three types of polioviruses so that they were effective in inducing immunity to polio but weak enough not to cause disease.

A massive vaccination campaign began, in which Sabin’s oral polio vaccine (OPV) was fed to 10 million Soviet children. Unlike the Salk trials of 1954 in the United States, the trial of Sabin’s vaccine used no unvaccinated control group.

The OPV had several advantages over the Salk vaccine (IPV).

• It produced an immune response faster than Salk’s vaccine, which meant that it could be used to respond to an epidemic.
• Because it entered the mouth, it traveled through the digestive system in the same manner as the wild virus. Vaccine recipients shed weakened vaccine virus in their stools, which sometimes had the effect of weakly immunizing those around them.
• OPV, often delivered on a sugar cube and eaten, was easier to give than the Salk vaccine, which was injected.

The IPV, however, retained one major advantage over the OPV: The killed viruses in IPV cannot revert to virulent forms as can the viruses in OPV. And in another resprect, the two vaccines are basically the same: The IPV is as good at OPV in preventing polioviruses from spreading through the bloodstream.

Over the next several decades, the medical world would continue to weigh the advanatages and disadvantages of the two vaccines.

A massive rubella outbreak in the United States initially failed to draw serious attention. A Time magazine article encouraged rubella parties, even recommending strategies so that “especially all the little girls get the infection.”

Unfortunately, despite warnings about keeping infected children away from pregnant women, nearly 50,000 women in vulnerable stages of their pregnancies were infected with rubella during the outbreak, leading to thousands of miscarriages and even more children being born with severe damage. At least 8,000 were born deaf, 3,500 deaf and blind; the total number of congenital rubella syndrome cases reached 20,000.

Over the course of the outbreak the country tallied approximately 12.5 million cases of rubella and more than 2,000 deaths. Resulting medical costs reached the billions.

The U.S. government licensed Merck’s combined trivalent measles, mumps, and rubella vaccine (MMR).

Combination vaccines have several advantages over single vaccines. They reduce the need for several separate injections, and they reduce costs of stocking and shipping multiple containers. Combination vaccines can help improve overall vaccination rates by simplifying the vaccination process.

The last wild human case of variola major occurred in the village of Kuralia, Bhola Island, Barisal district, Bangladesh. Rahima Banu was the sufferer. She was two years old at the time and made a full recovery, although she was scarred.

The World Health Assembly accepted the WHO Global Commission’s recommendation and declared the world free from smallpox.

On August 20, 1994, the Pan American Health Organization had reported that three years had passed since the last case of wild polio in the Americas. A three-year-old Peruvian boy, Luis Fermín, had the last registered case there.

The International Commission for the Certification of Poliomyelitis Eradication in the Americas examined this report as well as extensively reviewing lab and surveillance data. Based on the results of these analyses, wild poliovirus was declared eliminated from the Americas in September 1994, making the Americas the first World Health Organization Region to meet the goal of polio elimination.

Continuous transmission of measles was halted in the United States. However, U.S. residents remained at risk for infection from imported cases.

Fourteen years after the launch of the global eradication program, the World Health Organization declared polio eliminated in Europe on June 6, 2002.

The last case of wild polio in Europe occurred in a young boy. Melik Minas, who lived in Turkey, contracted polio in November 1998. Minas, who had not been vaccinated, was paralyzed as a result of the infection—although he did partially recover.

The United States Food and Drug Administration licensed a quadrivalent human papillomavirus (HPV) vaccine for use in 2006. The same year, the Advisory Committee on Immunization Practices recommended it for all US girls age 11-12 and up. In 2011 the vaccine would be recommended for boys age 11-12 and up. 

The vaccine protects against the two most prevalent cancer-causing HPVs and two wart-causing strains. HPVs cause almost all cervical cancers, and they can also cause anal and head and neck cancers in males and females, vaginal cancers, and penile cancers.

A bivalent HPV vaccine, recommended for females, protecting only against cancer-causing HPV types would be approved in 2009. A nine-valent vaccine would be licensed in 2014 and recommended in 2015. All licensed HPV vaccines are subunit vaccines, meaning they use only part of HPVs and cannot infect body cells. The vaccines use L1 protein that self-assembles to form empty shells that resemble HPV virus-like proteins.

Adolescents who begin HPV vaccination before age 15 need two doses of vaccine delivered at 0 and 6-12 months; those who begin on or after the 15th birthday need three doses of vaccine delivered at months 0, 1-2, and 6.

The World Health Organization Region of the Americas achieved a milestone in disease elimination – the Pan American Health Organization on September 27, 2016, declared the Americas to be free of endemic measles. The Region of the Americas is the first of the six WHO regions to eliminate transmission of measles. The United States was certified measles-free in 2000, and the last cases of endemic measles were reported in other countries of the region in 2002. The International Expert Committee for Documenting and Verifying Measles, Rubella, and Congenital Rubella Syndrome Elimination in the Americas was responsible for collecting reports from region countries to certify that measles had in fact been eliminated. 

Two-dose measles vaccine coverage in the Americas was estimated at only 46% in 2013, and lower than several other regions, and yet the Americas were able to achieve elimination before the others. This may be due to consistently high regional MCV1 coverage, with region-wide rates of greater than 90% since 1998. This high MCV1 coverage was achieved via many years of programmatic catch-up, follow-up, and speed up immunization campaigns. These immunization activities resulted in a precipitous drop in measles incidence–from 320 cases per million population in the years 1980-86, to 170/million in 1987-1994, to 13/million in 1995-2002, to .2/million in 2003-2009 (incidence figures in recent years include non-endemic transmission from imported cases).

On December 14, 2020, the first of 2.9 million doses of the Pfizer BioNTech mRNA vaccine against the novel coronavirus causing the COVID-19 pandemic was given to Sandra Lindsey, . Eight days later, New Jersey, the first of six million doses distributed that first week. The next day, on December 23, Drew Weissman, MD, PhD, and Katalin Karikó, PhD, with their research into mRNA vaccine technology.